In diabetes, the death of insulin-producing [unreadable]-cells in the pancreas by apoptosis leads to insulin dependence. Yet, the events that promote [unreadable]-cell death are still not fully understood. It is essential to increase our basic knowledge of the processes regulating [unreadable]-cell survival in order to develop novel and efficient therapies for diabetic patients. Evidence suggests that the female hormone, 17[unreadable]-estradiol (estradiol), protects insulin production and prevents diabetes. Although estradiol acts primarily via two distinct estrogen receptors (ERs), ERa and ER[unreadable], the individual contributions of these ERs in protecting [unreadable]-cell survival have not been established. Our long-term goal is to determine how to protect insulin production in diabetic patients by modulating estrogen signaling pathways in a gender non-specific manner. Our objective for this application is to elucidate the respective roles played by ERa, ER[unreadable], and non-classical estrogen actions in [unreadable]-cell survival and insulin production in vivo, through the use of genetic mouse models. Based on the preliminary data we have generated, our hypothesis is that ERa protects [unreadable]-cell survival;whereas, ER[unreadable] reduces ERa function and provokes [unreadable]-cell apoptosis. In order to test this hypothesis, we will first use a [unreadable]-cell ERa deficient mouse ([unreadable]ERaKO) to demonstrate that selective elimination of ERa in [unreadable]-cells impairs insulin production and provokes diabetes. Next, we will study a [unreadable]-cell ER[unreadable] deficient mouse ([unreadable]ER[unreadable]KO) to demonstrate that conversely, selective elimination of ER[unreadable] in [unreadable]-cells improves insulin production and prevents diabetes. Finally, we will create a combined [unreadable]-cell specific ERa/ER[unreadable] knockout mouse ([unreadable]ERa[unreadable]KO). Using this last model we will demonstrate that in absence of the classical ERa and ER[unreadable] in [unreadable]-cells, estradiol protects insulin production and prevents diabetes via non-genomic actions involving a novel membrane ER. Through the proposed research - which is the first investigation of ERs in [unreadable]-cell survival in vivo - we plan to demonstrate that classical and non-classical estrogen receptors are important to [unreadable]-cell survival in vivo, and therefore represent viable targets for therapeutic intervention.